tbuckley/cabot-search huggingface dataset:
NIMG-23. AI-BASED CONNECTED COMPONENT MARKERS OF BRAIN PERITUMORAL MICROENVIRONMENT USING WATER RESTRICTION INFORMATION
Authors: Zahra Riahi Samani, Drew Parker, Hamed Akbari, Ronald L Wolf, Steven Brem, Spyridon Bakas, Ragini Verma
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Glioblastoma is the most aggressive adult brain tumor, with heterogeneous neoplastic cell peritumoral infiltration. Characterization of this infiltrative peritumoral heterogeneity is an unmet clinical need that could contribute to strengthening our understanding of this disease. We propose novel AI-based markers of infiltration using deep-learning (DL) based on water restriction caused by infiltration, identified by diffusion tensor imaging (DTI). These markers could contribute to precision/personalized medicine, towards influencing clinical decision-making, including planning for biopsies, surgery, and radiation. METHOD: We automatically extracted peritumoral patches from free water volume fraction maps (FW-VF) of a retrospective cohort of 44 brain metastases and 66 glioblastomata patients and labelled them as high- and low- free water, respectively. An AI/DL model was then trained on these patches to distinguish differences in water restriction. Our trained AI/DL model was then applied on FW-VF of 264 hold-out glioblastoma patients (survival:0.43-76.9 months, age:21-88, 104 females) to generate a peritumoral microenvironment index (PMI) map quantifying infiltrative heterogeneity. Connected components (CCs) of high PMI values were calculated and their descriptive characteristics of size, number, shape, directionality, and spatial location, were extracted as AI-based markers. Gaussian mixture model clustering was then applied on these markers to determine if their representative infiltrative peritumoral heterogeneity can capture overall survival differences, by partitioning the patients into three clusters: low, moderate, and high risk. RESULTS The log-rank test yielded significant differences (p&amp;lt; 10-5) between low- and high-risk patients, (HR= 0.47, 95% CI:0.34-0.65; P&amp;lt; 0.005). Average PMI values were significantly greater in high-risk patients (P&amp;lt; 0.05). CONCLUSION We introduced novel AI-based markers of infiltration in the peritumoral microenvironment, using information of water restriction extracted from DTI. Our proposed markers can capture overall survival differences, based on the patterns of infiltration using DTI-based characterization of the water restriction, that show promise as clinically relevant prognostic biomarkers.
EXTH-08. DEVELOPMENT OF NOVEL HISTONE DEMETHYLASE INHIBITOR AGAINST DIPG
Authors: Amreena Suri, Srinivasan Venkatesan, Takahiro Sasaki, Yukitomo Ishi, Jun Watanabe, Kouki Abe, Frank H Ebetino, Alison J Frontier, Rintaro Hashizume
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of most the devastating pediatric brain tumors, and virtually all patients die within two years after diagnosis. It has been shown that targeted inhibition of JMJD3 demethylase activity by GSK-J4 results in restored K27 methylation and a significant delay of tumor progression and prolonged animal survival in intracranial DIPG patient-derived xenograft (PDX) models. Because of its promising anti-tumor activities, GSK-J4 has been used to treat many kinds of tumors in preclinical models including leukemia, lymphoma, neuroblastoma, prostate, and gastric cancer, and DIPG; however, GSK-J4 is not yet in clinical development. The major challenge for GSK-J4 in clinical development is that GSK-J4 is a prodrug and is rapidly converted in vivo to the active drug GSK-J1, which has restricted cellular and brain permeability. Hypothesis: We hypothesize that development of a stable GSK- J1 analog that offers good cellular and brain transport is essential to improving in vivo efficacy and is required for clinical application of this class of compounds. METHODS We developed a novel alcohol derivative of GSK-J1, UR-8, as a lead anti-cancer agent through our screening and drug development activities. RESULTS UR-8 has demonstrated selective cytotoxic activity against human K27M DIPG cells in vitro and apparently transported the brain to a useful extent based on its in vivo bio-distribution and effectiveness. CONCLUSION UR-8 showed greater anti-tumor activity and survival benefit than that obtained by GSK-J4 treatment in intracranial DIPG PDX models.
EXTH-90. HDAC INHIBITOR, CAY10603, IS A POTENT RADIOSENSITIZER IN MENINGIOMAS
Authors: Clemens Oliver Hanemann, Juri Na
Journal: Neuro-Oncology (2022)

Abstract Developing and evaluating potential radiosensitisers to enhance therapeutic efficacy are urgently needed due to the lack of efficient chemotherapy for meningioma. Histone deacetylase (HDACs) expression is generally increased in many cancer types and regulate the expression of numerous proteins involved in tumorigenesis. Targeting HDAC using HDAC inhibitor (HDACi) represent promising radiosensitisers that affect various biological processes, such as cell survival, apoptosis, and DNA repair. Recently, one of the HDAC inhibitor, AR42 monotherapy trials for patients with neurofibromatosis type2 started Nov 2021. However, we were not able to detect the actual HDAC downregulation after applying AR42 (0.5-2 μM) in immortalised meningioma. Hence, we investigated whether pretreatment with the hydroxamate-based HDAC6 inhibitor, Cay10603, impacts HDAC expression, radiation-induced DNA double-strand break (DSB) induction, cell survival, and cell cycle arrest in both immortalised and human meningioma cell lines. Cay10603 at nanomolar level (100 nM) was treated prior to high energy x-ray irradiation (2 Gy) by a medical linear accelerator (LINAC). We found that surviving rate was synergistically decreased after combination treatment of Cay10603 and radiation. Combination therapy induced DNA damage with activation of histone gH2AX and increased G2/M arrest compared to drug or radiation alone. To focus on the mechanisms of action of HDAC6 inhibition followed by radiation, we further investigated nuclear localisation of beta-catenin levels. The results showed the beta-catenin in the nucleus was suppressed after combination therapy. Our findings demonstrate a potential therapeutic strategy of Cay10603 to improve the radiosensitization for meningiomas.
DDEL-10. ULTRASOUND-ENHANCED DRUG DELIVERY IN HUMANS ALTERS ENDOTHELIAL PHENOTYPE AND PERTURBS THE ULTRASTRUCTURE OF THE BLOOD BRAIN BARRIER
Authors: Andrew Gould, Farida Korobova, Victor Arrieta, Christina Amidei, Michael Canney, Li Chen, Roger Stupp, Adam M Sonabend
Journal: Neuro-Oncology (2022)

Abstract The use of low-intensity pulsed ultrasound with concomitant injection of microbubbles (LIPU/MB) achieves local and reversible opening the blood-brain barrier (BBB), enhancing the delivery of systemically administered drugs to the brain parenchyma. Electron microscopic studies conducted in animals proposed that LIPU/MB enhances paracellular diffusion across the cerebral vasculature, by disrupting tight junction proteins between endothelial cells, as well as enhancement of caveolar transcytosis. The effects of LIPU/MB on the ultrastructure of the human BBB and cerebral endothelial phenotype have not been systematically investigated. Here we report a first in-human electron microscopic study, examining endothelial phenotype and BBB ultrastructure in the peri-tumoral brain of humans after undergoing LIPU/MB-enhanced drug delivery. Non-eloquent peritumoral brain was biopsied at different time points (4-63 minutes) following an intraoperative LIPU/MB procedure in three patients who underwent a surgical resection of recurrent glioblastoma through a phase I clinical trial [NCT04528680]. Transmission electron microscopy was used to examine cross sections of the microvasculature and associated components of the BBB. We observed a significant (P = 0.0397) time-dependent decrease in the frequency of endothelial caveolae immediately after sonication compared to non-sonicated control vessels, which resolved within 1 hour of treatment. We also observed a time-dependent increase in membrane-bound vacuoles in the endothelial cytoplasm following sonication (P = 0.0002, one-way ANOVA). Sonicated blood vessels occasionally showed swollen astrocytes, convoluted luminal protections, and lightening of otherwise dense tight junction proteins, not frequently observed in non-sonicated biopsies from the same patients. Our study shows that LIPU/MB changes the endothelial phenotype within the cerebral vasculature, and suggests the accumulation of vacuoles in endothelial cells after BBB opening.
CTIM-23. DOSE ESCALATION TRIAL OF FC-ENGINEERED ANTI-CD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY WITH D2C7-IT VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMAS (RMGS)
Authors: Annick Desjardins, Vidya Chandramohan, Daniel Landi, Katherine B Peters, Margaret Johnson, Mustafa Khasraw, Justin Low, Stevie Threatt, Chevelle Bullock, James E Herndon II, Eric S Lipp, John Sampson, Allan Friedman, Henry S Friedman, David Ashley, David Knorr, Jeffrey Ravetch, Darell Bigner
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND D2C7-IT, a novel immunotoxin-based cytotoxic therapy, targets epidermal growth factor receptor (EGFR) and mutant EGFR variant III. In preclinical studies, D2C7-IT kills tumor cells and prolongs survival, but is unable to generate cures in all animals. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. Eliminating glioblastoma immunosuppression via CD40 co-stimulation is anticipated to enhance D2C7-IT-induced antitumor responses. In murine glioma models, CED of D2C7-IT+αCD40 generated cures and long-term tumor-specific adaptive immunity. Hence, we are conducting a phase 1 trial of D2C7-IT+2141-V11 (αhuman-CD40) administered via CED in rMG patients. METHODS Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing doses of 2141-V11 to determine the maximum tolerated dose when administered sequentially following D2C7-IT (166,075 ng) via CED at 0.5 mL/hr. Five dose levels (DLs) are evaluated (2141-V11 at: #1: 0.70 mg; #2: 2.0 mg; #2**: 3.0 mg #2*: 4.0 mg; #3: 7.0 mg). RESULTS As of May 29, 2022, 13 patients were treated (3 patients on DL1, DL2, and DL2**; 2 patients on DL3 and DL2*). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 with DL3 and DL2* (fever, neurologic symptoms). All patients remain alive 0.7-10.6 months after therapy. Grade ≥ 2 AEs due to D2C7-IT+2141-V11 include: headache (grade 3, n = 1; grade 2, n = 4); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1); dysphasia (grade 3, n = 1); seizures (grade 2; n = 2); fever (grade 2; n = 2); and one each of grade 2 depressed level of consciousness, fatigue, and concentration impairment. Enrollment is ongoing. CONCLUSIONS Intratumoral administration of D2C7-IT+2141-V11 via CED is safe, encouraging efficacy results are observed.
DDDR-05. ERK INHIBITION INCREASES SENSITIVITY TO ANTI-PD-1 THERAPY IN A MOUSE MODEL OF BRAF MUTANT MELANOMA BRAIN METASTASIS
Authors: Magali de Sauvage, Naema Nayyar, Consuelo Torrini, Edwin Nieblas-Bedolla, Priscilla Brastianos
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Immune checkpoint inhibitors (ICI) have revolutionized the landscape of cancer treatment, including brain metastases. However, only a subset of patients with brain metastases respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, a key regulator of cell processes, are frequently found in brain metastases. LY3214996 (LY321) is a selective ERK 1/2 inhibitor that inhibits MAPK signaling and leads to regression of extracranial disease in preclinical models. Our objective was to evaluate whether with ERK inhibition (ERKi) can improve the efficacy of ICI in preclinical models of brain metastases. METHODS We tested sensitivity to LY321 in a BRAFV600E mutant, ICI resistant murine melanoma cell line (D4M) both in vitro and in vivo. To model brain metastases in vivo, we implanted D4M cells subcutaneously with subsequent intracranial implantation three days later. The treatment arms included LY321 and anti-PD-1 combination therapy, single agent therapies, and respective controls. We tested the efficacies of 2-week versus 4-week LY321 treatments, as well as 3-week treatment in an independent experiment. RESULTS D4M demonstrates in vitro sensitivity to LY321 (IC50 value of 4.75 µM). Our model demonstrated that LY321 in combination with anti-PD-1 improves both intracranial and extracranial disease control. Increased survival with combination therapy was observed with 3-week and 4-week LY321 administration. While individually, LY321 and anti-PD-1 produced better survival outcomes than control groups, combination therapy significantly outperformed both monotherapies. CONCLUSION Previous studies demonstrated that LY321 has minimal intracranial activity. However, we found that ERKi reduces intracranial tumor burden, with improved efficacy in combination with ICI in immunocompetent mice. Together, these data suggest that ERKi increases sensitivity to ICI therapy in pre-clinical brain metastasis models. Further investigation is needed to elucidate the mechanisms of this therapeutic approach, and to ultimately determine whether this combination will improve patient outcomes.
DDEL-06. HEAT-ACTIVATED DOXORUBICIN UPTAKE FACILITATED BY LASER INTERSTITIAL THERMAL THERAPY
Authors: Prazwal Athukuri, Karina Moreno, Yuhui Yang, Malcolm McDonald, Sungho Lee, Khatri Latha, Anantha Marisetty, Ganesh Rao
Journal: Neuro-Oncology (2022)

Abstract Although surgery has been shown to provide a survival benefit in patients with glioblastoma multiforme (GBM), tumor location and geometry may restrict maximal resection. Additionally, the margin of resection cavity contains infiltrating tumor cells that result in recurrence and therapy resistance. Laser interstitial thermal therapy (LITT) is a treatment modality that uses thermal energy to destroy tumor cells. LITT is useful for tumors that are not appropriate for conventional surgical resection. Our laboratory has developed a LITT model to study LITT in a genetically engineered mouse model of GBM. The combination of heat activated nanoparticles and LITT represents an opportunity to target the infiltrating tumor margin, extending the treatment penumbra. We hypothesized that heat-activated liposomes containing doxorubicin (ThermoDox, Celsion) would demonstrate infiltration into the brain parenchyma after treatment with LITT. We treated tumor-bearing mice with LITT or sham (laser fiber implanted but not activated) after either ThermoDox (5mg/kg) or PBS infusion, 30 minutes before performing LITT or sham treatment. We euthanized these mice 1 hour after LITT or sham treatment, harvested brains, and performed immunofluorescence to identify doxorubicin in parenchymal cells. Doxorubicin was identified in 100% of mice treated with LITT following ThermoDox administration which is in contrast with groups treated with LITT and PBS, sham and ThermoDox, and sham and PBS. Here, we show that heat-activated nanoparticles are disrupted through hyperthermia followed by the release of doxorubicin only in the presence of hyperthermia, which paves way for the clinical use of ThermoDox as adjunct chemotherapy following LITT in treatment-resistant GBM treatment.
RADT-36. MANAGEMENT OF PATIENTS WITH METASTATIC CENTRAL NERVOUS SYSTEM (CNS) GERMINOMA; A LITERATURE REVIEW
Authors: Mohammad Abu-Arja, Margaret Shatara, M Fatih Okcu, Susan McGovern, Jack M Su, Mohamed Abdelbaki
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND No consensus exists on the optimal irradiation volume/dose for patients with metastatic CNS germinoma. We reviewed the literature for a potential association between different treatment modalities and survival. METHODS We searched PubMed for studies on patients with primary metastatic CNS germinoma including detailed survival outcome data. We used the Kaplan-Meier method to estimate event-free survival (EFS) rates and log-rank test for comparison among treatment modalities. RESULTS We identified 124 patients from 38 studies published between 1990 and 2021. The median age of presentation was 15 years (range: 1.5–47 years). Treatment modalities included: chemotherapy only (n = 5), radiotherapy only (n = 31), and radio-chemotherapy (n = 88). Radiotherapy modalities included: craniospinal irradiation (CSI) (n = 69), whole-brain irradiation (WBI) (n = 19), whole ventricular irradiation (WVI) (n=16), focal and spine irradiation (n = 5), focal irradiation only (n = 9), and not specified (n = 1). The median focal irradiation dose was 36.6 Gy (range:19.5-59.8 Gy). The median doses for CSI, WBI, and WVI were 24 Gy (range: 10.8-49 Gy). Eighteen patients relapsed, 111 were alive without disease, 2 were alive with disease, and 12 died of disease. The median follow-up time was 5 years in survivors. Four patients who received only chemotherapy relapsed. Five-year EFS rates were similar in patients who received chemo-radiotherapy and radiotherapy alone (89%, 95%CI 81-97%, vs 88%, 95%CI 74-100%, p = 0.6). Patients who were treated with CSI had a longer 5-year EFS compared to patients treated with other modalities (92%, 95%CI 84-100% vs 80%, 95%CI 64-94% p = 0.03). EFS was similar in patients treated with CSI whether they received ≥ 24 Gy or less. CONCLUSION CSI is required to achieve prolonged relapse-free survival (RFS). CSI dose of &amp;lt; 24 Gy may be sufficient to achieve sustained RFS. Future trials are needed to evaluate the potential role of neoadjuvant chemotherapy in reducing the dose/volume of irradiation in patients with metastatic CNS germinoma.
NIMG-94. A RARE CASE OF INFRATENTORIAL CEREBELLAR VERMIS MULTINODULAR AND VACUOLATING NEURONAL TUMOR
Authors: Jerica Lomax, Edward Kuoy, Xiao-Tang Kong
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Multinodular and vacuolating neuronal tumor (MVNT) is a rare entity that was first recognized by the World Health Organization Classification of Tumors of the Central Nervous System in 2016. The majority of MVNT cases reported were supratentorial in location and only a small subset of cases included infratentorial involvement. In the supratentorial, MVNT is often a nidus for seizure and surgical resection is for seizure control. Infratentorial MVNT lesions are typically not or only mildly symptomatic; thus, surgical intervention may not be warranted. Here we describe the clinical course of a patient who was found to have a cerebellar vermis lesion that consistent with infratentorial MVNT. CASE REPORT A 41-year-old man sought care due to new onset headache. A brain magnetic resonance imaging (MRI) exam revealed a coalescence of bubble-like cystic lesions in the cerebellar vermis that were T1 hypointense, T2/Flair hyperintense without contrast enhancement. Initially, the lesions were attributed to neurocysticercosis but work-up was not supporting the diagnosis. MRA of head and neck found no cerebral stenosis or vascular malformation. The unique MRI features support infratentorial MVNT diagnosis. Disease course, work-up and MRI features are not consistent with low grade glioma, subacute ischemia infarct, demyelinating disease or chronic fungal or parasite infection. Brain MRI surveillance has completed every 6 months; no interval change to the cerebellar vermis lesions has been seen over past two years. Clinically, the patient has been doing well and his headache has resolved. DISCUSSION MRI features of MVNT are predominantly mixed solid and cystic, bubble-like, T2/Flair-hyperintense, T1 hypointense lesions in the deep cortical region and superficial white matter without contrast enhancement. This case demonstrates that although no specific criteria to diagnose MVNT, neurologists and neuro-oncologists should be aware of the distinguishing radiographic features, which can help patients avoid unnecessary testing and potentially harmful interventions.
EXTH-16. THE ORAL IRON-MIMETIC GALLIUM MALTOLATE SUPPRESSES TREATMENT-RESISTANT GLIOBLASTOMA – IN VIVO VALIDATION
Authors: Mona Al-Gizawiy, Robert Wujek, Melissa Prah, Jennifer Connelly, Christopher Chitambar, Kathleen Schmainda
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND We previously reported on our in vitro and in vivo studies using the metallocompound gallium maltolate (GaM) to target glioblastoma (GBM). We demonstrated a profound cytotoxic effect in vitrov and in vivo. Additionally, our preliminary in vivo data suggested a substantial inhibitory effect on tumor growth, as well as a significant extension of disease-specific survival (OS). Here, we further validate the inhibitory effects of GaM in vivo. METHODS In vitro irradiated adult GBM U87-MG cells were stereotactically implanted into the right striatum of male and female athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50 mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC,). Statistical analyses included Kaplan-Meier survival plots, linear mixed model (LMM) comparisons, and t-statistic for slopes comparison (as indicator of tumor growth rate). RESULTS Median OS for the male pilot cohort (5 control, 5 GaM) was 28 and 51 days, respectively; 31 and 59 days for the male replication cohort (1 control, 3 GaM); 37 and 48 days for the female replication cohort (6 control, 7 GaM). GaM-treated xenograft tumors grew significantly slower than control tumors with sex and time dependent growth rates. No significant differences were seen between male and female cohorts in both control and treatment groups at all timepoints. Hence, subsequent analyses were performed on pooled data. Median OS was 30.5 days and 48 days for control and GaM groups, respectively (p &amp;lt; .001). A strong correlation between treatment and survival (Χ2 = 6.238187; p = .0125) and tumor growth suppression (LMM; p &amp;lt; .0001) was evident. CONCLUSION We have successfully validated the inhibitory effects of GaM on GBM growth in vivo.